Lipid metabolism Chapter 26 Chem 454: Biochemistry II University of Wisconsin-Eau Claire Chapter 26 Chem 454: Biochemistry II University of Wisconsin-Eau Claire

Lipid metabolism

Basic TAG synthesis

Basic Phospholipid Activated Precursor synthesis e.g. PI

Other Basic Phosphoglyceride synthesis reactions

Basic sphingolipid synthesis reactions

Sterol Metabolism and Coronary Artery Disease

Big Picture: Exogenous Cholesterol Metabolism

Big Picture: Endogenous and Exogenous Cholesterol Metabolism

Cholesterol Synthesis

HMG-CoA Reductase Mevalonic acid

Regulation of Cholesterol Metabolism: HMG-CoA reductase 1.Reductase mRNA; SREBP pathway 2.mRNA translation 3.Reductase degradation; sensing membrane cholesterol 4.Reductase Phosphorylation

Regulation of Cholesterol Metabolism: HMG-CoA reductase (SREBP) HMG-CoA reductase, etc

Lipid Transport-LDL

Lipid Transport

Lipid Transport-Other lipoproteins See HDL Structure apo A-I

The LDL receptor See Clathrin Structure Here

The LDL receptor

Cholesterol and CORONARY ARTERY DISEASE HOW DOES IT HAPPEN AND HOW CAN YOU STOP IT?

CAD-Risk Factors High [LDL] –DIET –PARENTS (see Science 18 May 2001: Vol no. 5520, pp )PARENTS Smoking Type I and II diabetes High Blood Pressure

But it’s not straightforward… To understand where this complexity can lead in a simple example, consider a steak--to be precise, a porterhouse, select cut, with a half-centimeter layer of fat, the nutritional constituents of which can be found in the Nutrient Database for Standard Reference at the USDA Web site. After broiling, this porterhouse reduces to a serving of almost equal parts fat and protein. Fifty- one percent of the fat is monounsaturated, of which virtually all (90%) is oleic acid, the same healthy fat that's in olive oil. Saturated fat constitutes 45% of the total fat, but a third of that is stearic acid, which is, at the very least, harmless. The remaining 4% of the fat is polyunsaturated, which also improves cholesterol levels. In sum, well over half--and perhaps as much as 70%--of the fat content of a porterhouse will improve cholesterol levels compared to what they would be if bread, potatoes, or pasta were consumed instead. The remaining 30% will raise LDL but will also raise HDL. All of this suggests that eating a porterhouse steak rather than carbohydrates might actually improve heart disease risk, although no nutritional authority who hasn't written a high-fat diet book will say this publicly. Science 30 March 2001: Vol no. 5513, pp

Parents !

Not all in the diet. The quartet of hypercholesterolemias. In these four monogenic diseases, the inability of defective LDLRs to remove cholesterol-carrying LDLs from plasma causes an increase in plasma LDL and the deposition of atherosclerotic fatty plaques in arteries, leading to heart disease. The mutant gene products of the cholesterol quartet are shown in red; also depicted are the points where their normal counterparts act in the cholesterol pathway. [Not shown are the intermediate density lipoproteins (IDL), which are highly atherogenic intermediates in the conversion of VLDL to LDL (Science 18 May 2001: Vol no. 5520, pp ).] Sterol transport defect

Coronary Artery Disease

Circulation Feb 18;95(4): Classic Model (Smooth muscle cells) (connective tissue)

Coronary Artery Disease

Coronary Artery Disease- Treatments Statins- HMG CoA reductase inhibitors

Coronary Artery Disease- Treatments Fiber/Cholestyramine/etc.

Coronary Artery Disease- Treatments Niacin Antiinflammatories Blood Pressure DIET!!! (sat/trans fats) Don’t smoke! others